rs61751290 — VWF c.7437+1G>T

VWF c.7437+1G>T — A Splice Signal Silenced in the Bleeding Brake

Von Willebrand factor (VWF) is a large multimeric glycoprotein that performs two essential jobs in hemostasis: it tethers activated platelets to sites of vascular injury, and it escorts coagulation factor VIII through the bloodstream, protecting it from premature degradation. Without adequate VWF, even minor wounds fail to seal promptly and surgical procedures carry elevated bleeding risk. The rs61751290 variant disrupts the VWF gene at a particularly vulnerable position — the first nucleotide of intron 43 of the canonical VWF transcript (NM_000552.5¹¹ NM_000552.5).

The reference allele at plus-strand position 12:5,976,110 is C, which corresponds to a G on the coding (minus) strand — precisely the G that forms the canonical GT splice donor dinucleotide²² GT splice donor dinucleotide
The GT at the start of virtually every intron in human genes is the mandatory signal recognized by the spliceosome; mutation here disrupts mRNA processing. The alternate T allele on the plus strand changes this coding-strand G to an A, converting the intact GT to AT — a sequence the spliceosome cannot recognize.

The Mechanism

Pre-mRNA splicing is carried out by the spliceosome, a large ribonucleoprotein complex that excises introns and joins exons to form mature messenger RNA. The process depends on highly conserved splice donor (5') and splice acceptor (3') sequences at each intron boundary. The canonical splice donor is GU (GT in DNA)³³ GU (GT in DNA)
Almost 99% of human introns begin with GT; even single-nucleotide changes at this position abolish splicing in the vast majority of tested transcripts. Destroying the +1G of the splice donor at intron 43 is predicted by Ensembl's Variant Effect Predictor to be a high-confidence loss-of-function (HC LoF) variant⁴⁴ high-confidence loss-of-function (HC LoF) variant
Ensembl VEP flags splice_donor_variant at the +1 position as HIGH impact; LOFTEE classifies it as high-confidence LoF because +1 mutations essentially always destroy splicing.

When the splice donor is ablated, one of two outcomes typically follows: exon 43 is skipped entirely (joining exon 42 directly to exon 44), or the intron is retained in the mature mRNA. Both outcomes disrupt the VWF reading frame downstream of exon 43, generating either a premature stop codon or a transcript that is degraded by nonsense-mediated decay (NMD). The net result is that one copy of the VWF gene produces little or no functional protein — reducing circulating VWF levels and impairing primary hemostasis.

This mechanism is not speculative: analogous VWF splice donor +1 variants — c.1156+1G>A, c.1729+1G>A, c.5455+1G>A, c.6798+1G>T, and c.7081+1G>A⁵⁵ c.1156+1G>A, c.1729+1G>A, c.5455+1G>A, c.6798+1G>T, and c.7081+1G>A
All classified Likely Pathogenic or Pathogenic in ClinVar for hereditary von Willebrand disease; retrieved April 2026 — are all classified as pathogenic or likely pathogenic in ClinVar for hereditary von Willebrand disease.

The Evidence

The rs61751290 variant itself has one ClinVar submission from the Academic Unit of Haematology, University of Sheffield (accession RCV000086885.1), with clinical significance listed as "not provided" — reflecting an early database entry without formal classification. No PubMed publications currently cite this specific rsid. The variant is extremely rare⁶⁶ extremely rare
ExAC reports one carrier in 120,180 chromosomes; GO-ESP reports one in 13,006; ALFA finds zero in 6,396; all ancestry-specific frequencies are essentially zero, appearing primarily in European populations when detected at all.

The classification of this variant is therefore based on mechanism rather than direct epidemiological evidence — a well-established approach for rare null alleles where functional consequences are unambiguous. The ACMG/AMP variant interpretation framework⁷⁷ ACMG/AMP variant interpretation framework
Richards et al., Genetics in Medicine 2015 classifies +1 splice donor mutations in genes where haploinsufficiency is a known disease mechanism as Likely Pathogenic (PVS1 + PM2), irrespective of allele frequency. VWF haploinsufficiency (reduced protein from one allele) is the molecular basis of type 1 VWD, which affects approximately 1% of the population.

The ISTH guideline-endorsed thresholds⁸⁸ ISTH guideline-endorsed thresholds
James et al. 2017; Nichols et al. 2008 NHLBI guidelines for type 1 VWD are: VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity (VWF:RCo) below 30 IU/dL (30% of normal) is diagnostic for VWD; 30–50 IU/dL with bleeding symptoms is also classified as VWD; 50–200 IU/dL is normal. Type 1 VWD typically presents with levels in the 20–50 IU/dL range. Heterozygous carriers of null alleles often have VWF:Ag around 50% of normal, with wide individual variation influenced by ABO blood group, thyroid status, estrogen levels, and physical stress.

Practical Actions

Most heterozygous carriers will have mild symptoms at most — easy bruising, prolonged nosebleeds, heavier menstrual periods, or longer bleeding after cuts. The key step is establishing whether this variant actually produces VWF levels below the diagnostic threshold (30 IU/dL) or the symptomatic range (30–50 IU/dL). A VWF panel — antigen, ristocetin cofactor activity, and factor VIII — provides that answer. Blood group O independently lowers VWF by approximately 25%, so group O carriers of this variant face a compounded deficit and are more likely to meet the diagnostic threshold.

Desmopressin (DDAVP) is highly effective in many type 1 VWD patients: it stimulates the release of VWF stored in endothelial Weibel-Palade bodies, transiently raising VWF 3- to 5-fold. Whether this response is adequate depends on individual VWF stores and must be established via a formal DDAVP trial before the drug is used in an emergency.

Interactions

ABO blood group is the strongest modifier of VWF levels: blood group O reduces VWF antigen by approximately 25% through enhanced clearance of von Willebrand factor. A carrier of rs61751290 who is also blood group O (associated with rs8176719 and rs1053878 in the ABO gene) faces a compounded deficit and is substantially more likely to have VWF levels in the diagnostic range for type 1 VWD. A second VWF null allele — for example rs61750630 (VWF C2362F) in trans — would produce type 3 VWD-like severe deficiency. Thyroid disorders, estrogen (whether endogenous or from hormonal contraception), and acute illness all transiently raise VWF, potentially masking the underlying deficit if laboratory testing is done during these states.